title: Treatment of neuroblastoma and rhabdomyosarcoma using RGD-modified liposomal formulations of patupilone (EPO906).
abstract: BACKGROUND
  Patupilone (EPO906) is a microtubule stabilizer with a potent antitumor effect. Integrin αVβ3-binding (RGD) liposomes were loaded with EPO906, and their antitumor efficacy was evaluated in two pediatric tumor models, ie, neuroblastoma and rhabdomyosarcoma.
  
  
  METHODS
  Integrin αVβ3 gene expression, RGD-liposome cellular association, and the effect of EPO906 and liposomal formulations of EPO906 on cell viability were assessed in vitro in human umbilical vein endothelial cells (HUVEC), in the RH-30 rhabdomyosarcoma cell line, and in the Kelly neuroblastoma cell line. In vivo, mice bearing neuroblastoma or rhabdomyosarcoma tumors were treated with EPO906, EPO906-liposomes, or EPO906-RGD-liposomes. Tumor growth, cumulative survival, and toxicity were monitored.
  
  
  RESULTS
  Integrin αVβ3 was highly expressed in HUVEC and RH-30, but not in Kelly cells. Accordingly, RGD-liposomes were highly associated with HUVEC and RH-30 cells in vitro, but not with the Kelly cells. EPO906 and its liposomal formulations inhibited HUVEC, RH-30, and Kelly cell viability to the same extent. In vivo, EPO906 1.5 mg/kg and liposomal EPO906 potently inhibited tumor growth in both xenograft models without triggering major toxicity. At this dose, liposomal EPO906 did not enhance the antitumor effect of EPO906 in neuroblastoma, but tended to have an increased antitumor effect in rhabdomyosarcoma. Using a lower dose of EPO906-RGD-liposomes significantly enhanced cumulative survival in rhabdomyosarcoma compared with EPO906 alone.
  
  
  CONCLUSIONS
  EPO906 shows a strong antitumor effect in neuroblastoma and rhabdomyosarcoma, without triggering major side effects. Its liposomal encapsulation does not alter its activity, and enhances cumulative survival when EPO906-RGD-liposomes are used at low dose in rhabdomyosarcoma.
authors.affiliation: Clinic IV, Pediatric Hematology and Oncology, Center of Pediatrics and Adolescent Medicine, University Medical Hospital Freiburg, Germany.
authors.forename: Karine
authors.initials: K
authors.lastname: Scherzinger-Laude
authors.forename: Carina
authors.initials: C
authors.lastname: Schönherr
authors.forename: Felicitas
authors.initials: F
authors.lastname: Lewrick
authors.forename: Regine
authors.initials: R
authors.lastname: Süss
authors.forename: Giancarlo
authors.initials: G
authors.lastname: Francese
authors.forename: Jochen
authors.initials: J
authors.lastname: Rössler
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D001835:Body Weight; D045744:Cell Line, Tumor; D002470:Cell Survival; D004337:Drug Carriers; D034261:Epothilones / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D005260:Female; D061307:Human Umbilical Vein Endothelial Cells; D006801:Humans; D039302:Integrin alphaVbeta3 / Q000378:metabolism; D053208:Kaplan-Meier Estimate; D008081:Liposomes / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D051379:Mice; D016513:Mice, SCID; D009447:Neuroblastoma / Q000188:drug therapy* / Q000473:pathology; D009842:Oligopeptides / Q000737:chemistry*; D012208:Rhabdomyosarcoma / Q000188:drug therapy* / Q000473:pathology; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D004337:Drug Carriers; D034261:Epothilones; D039302:Integrin alphaVbeta3; D008081:Liposomes; D009842:Oligopeptides; C047981:arginyl-glycyl-aspartic acid; C093788:epothilone B
keywords: integrin targeting; liposomes; patupilone; pediatric cancer